DE2617592A1 - NEW 2 SQUARE BRACKETS ON 4- (3-OXO- OR -HYDROXY-ALKYL) -PHENYL SQUARE BRACKETS ON -ALKANIC ACIDS AND THEIR NON-TOXIC SALT, THE PROCESS FOR THEIR PRODUCTION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Description

New 2 ~ / 4- (3-oxo- or -H; yάroxyΐιl · k3r · l) - phen.7l7 - alkali acids and their non-toxic salts, processes to their manufacture and pharmaceutical compositions containing them

According to the invention, new 2-./4-(3-OxO- or -hydroxyalkyl) -phenyl7-alkanoic acids are used and their non-toxic salts. These compounds are useful in treating symptoms of inflammation and pain in mammals, including humans valuable. The invention relates to these compounds, a process for their preparation and pharmaceutical compositions, which contain such a connection.

The aim of the invention is to provide new compounds which are useful as medicaments for the treatment of inflammation and pain in mammals. Another object of the invention is to create new connections that are called medicines

6098A6 / 1050

~ ² ~ 2 6 I 7 h 9 2

for the treatment of rheumatoid inflammation and pain are valuable.

It has now been found that compounds of the general formula I.

1 2

where R is a hydrogen atom and E. is a By droxy group

12 "5

represents, or R together with R represent an oxo group, R represents a lower alkyl group, R represents a hydrogen atom or represents a lower alkyl group and R represents a lower alkyl group and its non-toxic salts are valuable anti-inflammatory Have properties, both in acute inflammation or inflammation and subacute inflammation including those with rheumatic diseases and that they also have analgesic activity.

In addition, they generally have a greater degree of safety in anti-inflammatory therapeutic use, compared to ibuprofen, and have little or no other undesirable pharmacological activities leading to undesirable Lifting effects could give rise to.

In general formula I, R preferably represents a methyl group The following compounds represent typical examples of active compounds of general formula I above without, however, restricting the invention in any way :

609846/1050 ORIGINAL INSPECTED

2- / 4- * (3 ~ 0xobutyl) phenyXjpropionic acid, Z- [Ir- (3-Hydroxybuty X) phenyX / propionic acid, 2- / £ ~ (2 ~ IiethyX ~ 3-oxobutyX) phenyX / propionic acid, Z ~ £ h ~ (2-MethyX-3-hydroxybuty X) pheny! / Propionic acid, 2- / £ ~ (2-EthyX-3-oxobutyX) phenyX / propionic acid, 2 ~ / & - (2 ~ lthyX ~ 3-hydroxybuty X ) phenyX, / propionic acid, 2 - // J.- (2-PropyX «3-oxobuty X) pheny! ^ propionic acid, 2" / Jr * (2-Propy X- »3-hydroxybuty X) pheny X / pr op ionic acid, 2- ^ 4-, (2-Methy X-3 ~ oxopeni> yX) ph.eny! / propionic acid, ZP ^ " (2-Me tliy X - ^ - ^ iy dr oxy ρ enty X) pheny X "7pr opi onic acid, 2- £ 4- (2-lthyX-3-oxopen1; yX) phenyX / propionic acid, 2- / 4- (2-Xthy X-3-by droxypenty X) plieny X / propionic acid, 2- / ^ - (2-PropyX-3-oxop enty X) pheny X_ / propionic acid. 2-ßr ~ (2-Propy X ~ 3-hy droxypenty X) pheriy X / propionic acid,

enyX / propionic acid,

it is more preferable to use claJ3 R ^ alsofaXXs a HethyXgruppe in the general formula I darsteXXt. Particularly preferred compounds are 2- / 4- (2-MethyX-3-hydroxybutyX) phenyXjpropionic acid and 2- / 4- (2-lthyX ~ 3-hydroxybutyX) phenyX / propionic acid,

Although different from the connections of the common connection I. Stereοisofflere exist, the invention relates to aXXe stereo

Non-toxic algae of the compounds according to the invention

I are the SaXze with various well-known organizations or inorganic bases that are pharmaceutically acceptable can be used, examples of these bases are in particular the bases of the alkali metals, such as sodium, potassium, etc., of the alkaline earth metals, such as caleiua, magnesium, etc., and various basic amino acids. ]} ie basic amino acids B-lysine, I ^ -lysine, DL-lysine, D-hydroxylysine, 3> i3ydroxylysine, Dl-hydroxylysine, D-arginine, ir-irginine, DL-zirginine, D-ornithine, L-

Ornithine and DI ornithine.

According to the invention it is possible to obtain the compounds of the above formula I by using the the aldehyde (Ha) or (lib) to be produced is oxidized according to the following scheme:

(A)

CH ₂ COO-CH-CH-CH ₀ -

R ⁵ COCl

Friede1-Craft reaction

,, r- \ _{R ClCH 0} COOCH ₃ . / NaOCH ₇ CH ₅ COO-CH-CH-CH ₂ -ZQVcOR- ⁷ _ Z :

Darz en-Eondens at i on

CH ₅ COO-CH-CH-CH ₂ -

HO-CH-CH-CH ₀ -

_C CHCOOCH,

_C CHCOOCH,

V ³

hydrolysis

B09846 / 1 Q5Q

2 6 1 7 B 9 2

ft

HO-CH-CH-CH ₂ -

-C CHCOOH

- co.

ft

HO-OH-CH-CH ₂ -

-CHCHO. (Ha)

O = C-CH-CH,

R ^ COCl /

Friedel-Craft-Heaktion

ff
O = C- CH-CH ₂ -

-COR-HIGH ₂ CH ₂ OH

CH ₂ O

^ C-CH-CH ₂ - ^ r ^ -COR-

ClCH ₂ COOCH ₅ / NaOCH ₅ Darzen concensation

CEpO ^, γ

I * O-CH-CH ₀

CH ₂ O ^d

-C CHCOOCH,

V hydrolysis

ft

-C CHCOOH

- CO.

hydrolysis

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In the above reaction scheme or schemes R, R ^ and R- * have the meaning given above.

Oxidizing agents suitable for preparing the compounds of formula I from the aldehydes (Ha) or (lib) include for example hydrogen peroxide, potassium manganate, potassium dichromate, liatrium dichromate, nitric acid, silver oxide and oxygen in the presence of a catalyst such as silver oxide.

The reactions are carried out in different media, which are suitable with regard to the oxidizing agents and the aldehydes and the reaction temperature depends on the reactants. If the oxidizing agent is potassium dichromate or IT sodium dichromate becomes the aldehyde (Ha) where R is a hydroxy group is converted into the compound of formula I, wherein

1 2

R is oxidized together with R ei] group.

1 2

R together with R represent an oxo group in which the hydroxy

Furthermore, the compounds formed can be converted into the corresponding non-toxic salts in the customary manner.

Sensitive tests on the pharmacological activities of the compounds of Formula I above are given below. On the basis of the results, the anti-inflammatory activities and the acute at in rats are shown in Table 1 and the safety factor (the ratios of IiDc ₀ ^to to ED ^ q or to ED. Q) for the anti-inflammatory activities in rats and the analgesic activity in mice in Table 2

specified.

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(a) Inhibition of carrageenin-induced paw edema

According to the method of CA. Winter et al. (Proc.Soc.Exp.Biol.Med., 111, 544 (1962)) one hour after the oral administration of the test compounds to male Donryu rats of 140 + 10 g 0.1 ml of a 1 -fold garrage eninsuspens ion in physiological saline solution subcutaneously into the tendon skin of the right

Hind paw injected. The volume of the paw was measured before and three hours after the carrageenin injection. The threshold index the inflamed paw was calculated as follows:

Swelling index

/ average ^ / average X / paw volume three j - j paw volume before j I hours after the J \ of the injection J _s \ injection / \ S

(average volume of paw before injection)

The percent inhibition was calculated as follows:

Inhibition ($)

/ Swelling index of N _ / swelling index of ¹ N VY comparison rats / ™ ^ treated rats / -. . χ

(Swelling index of the comparison rats)

(b) Inhibition of intraperitoneal dye loss

According to the method of B.A. Whittle (Br. J. Pharmac. Chemother., 22, 246 (1964)) one hour after the oral administration of the test compounds on male Donryu rats of 160 + 10 g 0.5 ml of 0.5 # Evans blue dissolved in physiological saline injected intravenously. Mn minutes later they were intraperitoneally 0.2 ml of 3% acetic acid per 100 g of body weight is injected. The dye in the peritoneal exudate, which was removed 45 minutes after the acetic acid injection, was subjected to a spectro-

"ß Π 9 δ A 6/1 0 5 Q

subjected to photometric examination at 620 m / rev. The pro percent inhibition was calculated as follows:

Inhibition ($)

/ mean optical density \ · _ / "mean optical density) yyon control rats J ~ y of treated rats J ^.

- y. χ

(mean optical density of comparison rats)

(c) Inhibition of granuloma formation by the granulo-pocket method

Using the method of A. Robert and JE ITezamis (Acta. Endocrinol., 25 »105 (1957)), an air pocket of 180 + 10 g was formed subcutaneously on the back of male Wißter rats of 180 + 10 g and 1 ml of 1 fo Groton oil dissolved in cotton oil is injected into the ash. The compounds were then administered orally and the next day the compounds were administered orally to Tom at 9 a.m. and 4 p.m. for 6 days. On the day after the day of the last administration, the G-ranuloma pocket was removed and vyogued. The percent inhibition was calculated as follows:

Inhibition (fo)

/ medium Gev / layer of the \ / average weight of the granuloma ί of encryption J - f granuloma of behan- _ x equal rats s_ Vdelten rats

(mean weight of the granuloma of comparison rats)

(d) Acute toxicity

The compounds were tested on male Wistar rats of 200 + 10 g administered orally. The observation extended over 7 days.

(e) Inhibition of granuloma formation by the cotton pellet method

Awake the method of CA. Winter et al. (J. Pharmac. Exp. Ther.,

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141, 369 (1963)) were in male Donryu rats of 130 + 10 g two sterilized cotton pellets of 35 + 1 mg each subcutaneously aseptically embedded in the lateral abdomen. The compounds were then administered orally. From the next day they were Compounds administered orally at 9 a.m. and 4 p.m. for 3 days. The day after the last administration, the pellets were removed, dried and weighed to the weight of the around the pellet to determine the granuloma formed. The percent inhibition was calculated as follows;

Inhibition. ($ £)

/ mean weight of Λ / mean weight of \ (granuloma of comparative J - Γ granuloma of treated) _ V jatten J \ delten rats / ..qq

(mean weight "of the granuloma of comparison rats)

(f) Anaetic activity induced by acetylcholine Curvature method on the mouse

According to the method of S.S. Adams (Arch. Int. Pharmacodyn., 178, 115 (1969)) was given a weight of 20 + 1 g on male SLC-ICR mice Writhing by intraperitoneal injection of 0.1 ml per-10g Body weight of 7.5 mg per kg of acetylcholine, dissolved in physiological saline solution. The test connections were administered orally 60 minutes before the acetylcholine injection, after which the frequency of response or writhing for each animal was counted for 8 minutes. The percent inhibition was calculated as follows:

Inhibition ($)

/ mean frequency of the an \ / mean frequency of the \ ί Speaking of the comparison / - (addressing the behan-J

_ V mouse s Vdelten mouse y _x -ι qo

(mean frequency of response of the comparison mouse)

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Comment:

Compound A: 2- / 4- (2-methyl-3-o2: obutyl) p] ienyl7propionic acid,

Compound B: 2- / 4- (2-methyl-3-l ^ droxybutyl) pheny ^ propionic acid,

Compound C: Z- [Jt- (2-Ethy 1-3-ozobuty 1) pneny! ^ Propionic acid, Compound Ό: 2- / 4- (2-Ethy 1-3-hydroxybutyl) phenyl7propionic acid.

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Table 1

Anti-inflammatory activities and acute toxicity in rats

link

Effect on acute inflammation

Inhibition of carrageenin-induced paw edema

Dose (mg / kg)

Inhibition

CiO

Bihibition of the "" intraperitoneal dye loss

Dose (mg / kg)

Inhibition (30

Effect on subacute inflammation

Inhibition of granuloma formation by the G ranuloma pocket method

dose
(mg / kg)

Inhibition

acute toxicity

Dose (mg / kg)

died

treated

Connection A

31.7

22.3

250

Connection B

34.9

24.2

250

Connection 0

35.2

0.5.

22.7

125

Connection D

38.1

0.5 23.5

125

Ibuprofen
(Comparison)

10.

31.2

10

21.1

625

table 2

Safety factor (ratio of IrD ₅₀ to ED ₂₀ , ED ₃₀ or ED, _Q ) for the anti-inflammatory activities in rats and the analgesic activity in mice

"Link

Effeiet for the acute inflammation

Inhibition
of carrageenin-induced paw edema

^ED 40
'mg /

_k Ae

ED

Inhibition of the intraperir toneal dye loss

ED,

LD

Effect on subacute inflammation

Inhibition of G ranuloma formation by the ffranu lomtaschen method

'mg / .ÄS

LD ED

20th

Inhibition of granuloma formation by the Baumv / oll-f pellet method

^ED 20th

'mg /'

ι Ag

LD ₁

ED

20th

acute toxicity

LD

50

ng

analgesic d

activity

through the

Acetyl

choline-me-

method

ED,

Connection D

Ibuprofen _N
(Comparison)

2.5

16

52.8

42.8

O.3I

425.8

40.3 0.73

180.8

16.3

0.33

22nd

400.0

31.1

132

685

2.7

4.7

2 61 7 ^: -. 9 2 - 13 -

It follows from Tables 1 and 2 that the new 2- / 4- (3-oxo- or -hydro2-yalkyl) piienyl7alkanoic acids of the general formula I according to the invention have excellent anti-inflammatory and analgesic activities compared with ibuprofen. In particular, the effect on subacute inflammation is quite excellent and the safety factor (the ratio of IlDe ₀ ^{to ED} 20 ^ ' ^ ^{elc represents} the degree of safety is about ten times higher than that of ibuprofen. Therefore the compounds of formula I and their nontoxic salts very valuable as a medicament for the treatment of inf laminate ions and pain including that of rheumatism.

The new 2- / 4- (3-oxo- or -hydroxyalkyl) phenyl7alkanoic acids according to the invention of the formula I and their nontoxic salts can be administered in the usual manner in terabgabeformen. be formulated, to be administered both orally and parenterally, such as capsules, powders, granules, tablets, pills, suspensions, Emulsions, syrups, injections, suppositories, etc.

The dose of active ingredient to be administered will vary with the level of activity of the compound used. In general mammals are administered amounts of 1 to 10O mg / kg body weight per day in order to provide effective relief or control of inflammation and pain. It is therefore advantageous that such dosage forms contain the active ingredient contained in amounts of 10 to 200 mg per unit.

In particular, the formulation can be done as follows:

(a) In the case of solid forms of administration such as capsules, powders, granules, Pills, tablets, etc., the active compound is mixed with at least one inert diluent such as sucrose, lactose, starch, etc. mixed together. The forms of administration such as granules, pills, tablets, etc. can also contain other substances in addition to the inert diluent, for example binders such as a starch solution, gelatin oil

609846/1050

-H-

sung, Kethy! cellulose, microcrystalline cellulose etc. and Chopping agents (disintegrants) such as starch, agar, calcium cellulose glycolate etc. In the case of the tablets, the form of administration can also include lubricants such as magnesium stearate, Stearic acid, talc, etc. and may additionally, optionally be made with enteric coatings.

(b) In the case of liquid administration forms, such as suspensions, In emulsions, syrups, etc. the active compound is mixed with liquid vehicles such as water. Such forms of administration can also add additional substances such as suspending agents, emulsifiers or thickeners, for example Contain carboxymethyl cellulose, microcrystalline cellulose or tragacanth. Furthermore, the forms of administration additionally contain, for example, sweeteners and aromatic substances

(c) In the case of aqueous or non-aqueous injections, the active compound is mixed with water for injection or with non-aqueous injectable liquid vehicles, for example vegetable fat or oil, such as olive oil, sesame oil, soybean oil us \ "/., and organic solvents such as propylene glycol, ethanol, Glycerine, polyethylene glycol, etc. mixed. Such forms of administration may also contain additional substances, such as stabilizers, solubilizing agents, suspending agents, emulsifiers, buffering agents and preservatives. You can also get in shape of sterile, solid compositions can be prepared in sterile water or another sterile injectable The medium can be dissolved immediately before use.

(d) In the case of supositories, the active compound with generally known raw materials, such as cocoa butter, raurine butter, Glycerogelatin, macrogol, etc. mixed. Possibly

609846/1050

such forms of administration can also include additional substances, for example surface-active agents and preservatives contain.

Typical examples of pharmaceutical compositions are given below without, however, limiting the invention will.

1. Tablets

2- / 4- (2-methyl-3-hydro ^ butyl) pheny! ^ Propionic acid

lactose starch microcrystalline cellulose magnesium stearate

25.0 mg 56.0 mg 37.5 mg 30.0 mg 1.5 mg 150.0 mg / tablet

Tablets

2- / 4- (2-Ethy1-3-hydrozybutyl) phenyl7propionic acid

granulated lactose calcium cellulose glycolate magnesium stearate

25.0 mg 69.0 mg

5.0 mg

1.0 mg

100.0 mg / tablet

These tablets were made with the aid of the usual granulation using aqueous or non-aqueous liquid vehicles various binders or formulated by dry granulation.

The following examples illustrate the preparation of the compounds of the general formula I.

609846/1050

2 6 1 7 -S 9 2

example 1

Production of 2- / 4 ~ - (2-methyl-3-hydroxybutyl) - phenyl7propionic acid

(1) In a mixture of 50 ml of acetyl chloride, 90 g Aluminiuinchlorid and 200 ml of methylene chloride was added below 55 ⁰ O 61.8 g (2-methyl-3-acetoxybutyl) benzene are added dropwise in 30 minutes under stirring and at.

Bachdem the reaction mixture was stirred for 4 hours at 25 ⁰ C, it was poured into ice water and extracted with methylene chloride. The methylene chloride extract was then washed with dilute hydrochloric acid and the solvent was evaporated in vacuo. The obtained residue was fractionated by vacuum distillation to obtain 60 g of 4- (2-methyl-3-acetoxybutyl) phenylmethylketon were obtained in a yield of 80 fi ·

Kp 0.15 mmHg / 113 to 117 ^° C

IR (in substance) cm: ^) _c _ ₀ 1670 (aromatic ketone)

^ _{c = 0} 1720 (ester)

(2) In a mixture of 24.8 g of 4- (2-methyl-3-acetoxybutyl) -phenylmethy! Ketone, 21 g of methyl chloroacetate and 80 ml of hexane were stirred in a nitrogen stream at -5 to ⁰ ° C. within one hour 12 g of sodium methylate added. Ifachdem then the reaction temperature was raised for one hour at 25 ⁰ C, the mixture was stirred for 3 hours at 35 to 4O ⁰ C.

The mixture formed was then poured into ice water and extracted with diethyl ether. The diethyl ether extract was washed with water, dried and then evaporated in vacuo, 28.5 g of a mixture being obtained, consisting from methyl 1-3 / 4- (2-methyl-3-acetoxybutyl) phenyl7-2,3-epoxybutanoate and MetlTyl 3- / 4- (2-methyl-3-hydroxybutyl) phenyl 7-2,3-epoxybutanoate.

609 8 46/1050

2617S92 - 17 - ■

IR (pure) cm " ¹ : ^) _{c = 0} 1740 (ester)

0 0-H ³⁵⁵ ° <"

(3) 3 »5 g of sodium was dissolved in 60 ml of methanol and added to this

Solution was added the above-obtained mixture of 28.5 g joined "The resultant mixture was cooled to 10 ⁰ C, after which 3» 5 ml of water were added γ / urde flattens and allowed to stand at 25 ⁰ C over "was.

After removing the methanol by evaporation in a vacuum, the P residue was washed with diethyl ether and dissolved in water solved. The aqueous solution was acidified by adding dilute hydrochloric acid and then gradually heated under Eohlendioxidentwieklung and then heated to reflux for 1.5 hours.

After cooling, the reaction mixture was extracted with diethyl ether. The diethyl ether extract was with a washed and dried dilute aqueous sodium carbonate solution, and evaporated in a vacuum to obtain a crude product from 18g of 2 - ^ - (2-methyl-3-hydroxybutyl) phenyl7propionaldehyde was, yield $ 82 (calculated from the 4- (2-methyl-3-acetoxybutyl) phenylmethy! ketone).

Then the product obtained above was purified by column chromatography on silica gel, whereby 14 | 5 g of a pure product were obtained.

IR (pure) cm " ¹ : ^ _{c = 0} 1710 (aldehyde)

4 oH ^{5420 (} - ^0H)

MS m / e: 220 (M ⁺ ), 173 (M ⁺ - (CHO + H

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(4) To 200 ml of an ethanol solution containing 2.2 g of 2- / 4- (2-methyl-3-hydroxybutyl) phenyl7propionaldehyde were added 20 ml of an aqueous solution containing 5 g of AgNO-, and then afterwards and after stirring 55 ml of an in-Hatriimihydroxidlösung added.

After the mixture was stirred for 6 hours, it was filtered. The piltrate was then evaporated in vacuo concentrated and washed with diethyl ether. Afterward the material obtained was acidified by adding dilute hydrochloric acid and extracted with diethyl ether. That Diethyl ether extract was washed with water, dried and evaporated in vacuo, 1.9 g of the crude product 2- / 4- (2-I-ethy 1-3-hydroxybutyl) pheny ^ propionic acid, Yield 80 ^, were obtained.

The product was made from a mixed solvent of diethyl ether and η-hexane were recrystallized to obtain pure crystals.

Ϊ ¹ 85 - 88 ⁰ C

Elemental analysis for Cj, H ₂₀ O ,:

Calc .: C 71.16 #, H 8.53 fo Found: C 71.40 #, H 8.60 fo

IR (EBr) cm ~ ¹ : -J _{c =} 0.1700 (-COOH)

0-H

Example 2

Preparation of 2- / £ - (2-methyl-3-oxobutyl) phenyl7propionic acid

(1) Using (2-methyl-3-oxobutyl) benzene, the same procedure as in Example 1 - (1) was followed to obtain the 4- (2-methyl-3-oxobutyl) phenylmethy! Ketone to be obtained.

Zp 0.15 mmHg / 107 to 111 ⁰ C IR (pure) cm ": ^ q_q 1670 (aromatic ketone)

C = O ¹ ^ ⁰⁰ (a ^ '- ip ^ a'ti ⁸⁰¹¹⁶⁸ ketone)

60 98 46/1050

(2) 40.8 g of 4- (2-methyl-3-oxobutyl) phenyl methyl ketone, 20 g of ethylene glycol and 20 mg of p-toluenesulfonic acid were mixed and ^{stirred at 25 0} O overnight. Subsequently, the reaction water formed was removed by "evaporation in Yakuum while the temperature was maintained for 3 hours at 50 ⁰ C.

After the reaction mixture was made alkaline with a dilute aqueous sodium carbonate solution, it was extracted with diethyl ether. The diet ether extract was washed with water and dried and freed from the solvent by evaporation in a vacuum. The resulting liquid was fractionated by vacuum distillation to obtain 30 g of 4- (2-methyl-3-äthylendioxybutyl) phenylmethylketon were obtained in a yield of 60 fo.

IR (pure) cm "": Λ _{c = 0} 1670 (aromatic ketone)

(3) To a mixture of 24.8 g of 4- (2-methyl-3-ethylenedioxybutyl) · phenylmethy! Ketone, 21 g of methyl chloroacetate and 80 ml of n-hexane were stirred in a nitrogen stream at -5 to ⁰ ° C. within one hour added 12 g of sodium methylate. ' After this

. temperature _o

the reaction / was then raised for one hour at 25 C, the mixture was stirred for 3 hours at 35 to -40 ⁰ C.

The resulting mixture was poured into ice water and extracted with diethyl ether. The Diäthylätherextrakt was washed with water, dried and then evaporated in Yakuum to 30 g of 3-Z4 (2-methyl-3-äthylendioxybutyl) phenyl7-2,3-epoxybutanoat crude product in a yield of 98 to obtain fo.

IR (pure) cm "" ¹ : / j _{c = 0} 1740 (ester)

(4) 3 g of sodium were dissolved in 60 ml of methanol and the 30 g of methyl 1-3 / 4- (2-methyl-3-ethylenedioxybutyl) phenyl 7-2,3-epoxybutanoate obtained above were added to this solution. The resulting mixture was cooled to 10 ⁰ C, after which 3 ml water was added and then incubated overnight at 25 ° C

• 60S846 / 1050

was left standing.

After removing the methanol by evaporation in vacuo, the residue was washed with diethyl ether and then dissolved in water. The aqueous solution was acidified by adding dilute hydrochloric acid and then gradually heated with evolution of carbon dioxide and refluxed for a further 1.5 hours.

After cooling, the reaction mixture was washed with diethyl ether extracted. The diethyl ether extract was washed with a dilute aqueous sodium carbonate solution and dried and evaporated in vacuo, 16.3 g of a 2- / 4- (2-methyl-3-oxobutyl) pheny ^ propionaldehyde crude product were obtained; Yield $ 75 (calculated from 4- (2-Methy1-3-ethylenedioxybutyl) phenylmethy! Ketone). Then, the product obtained above was purified by column chromatography (silica gel) to obtain 9 g of the crude product.

IR (neat) cm "" ¹ : \ j _{C = Q} 1710

MS m / e: 218 (M ⁺ ), 189 (M ⁺ - CHO)

(5) To 200 ml of an ethanol solution containing 2.2 g of 2- / 4- (2-methyl-3-oxobutyl) phenyr7propionaldehyde 20 ml of an aqueous solution containing 5 g of AgHO ,, was added, and further 55 ml of sodium hydroxide solution were gradually added with stirring.

After the mixture was stirred for 6 hours, it was filtered. The filtrate was then concentrated by evaporation in vacuo and washed with diethyl ether. Afterward the material obtained was acidified by the addition of dilute hydrochloric acid and diethyl ether extracted. The ether extract was washed with water and dried and evaporated in vacuo to give 1.9 g of 2- / 3 - (2-Me thy 1-3-

609846/1050

oxobutyl) phenyl7propionic acid crude product in a yield of 80 io .

The product was purified by column chromatography (silica gel) purified to obtain 1.4 g of a pure oil.

IR (pure) cm " ¹ : \) _{0 = 0} 1690 (-COOH, ^ CO)

Example 3

Production of 2- / 4- (2-ethyl-3-hydroxybutyl) phenyl7propionic acid

(1) Using (2-ethyl-3-acetosybutyl) benzene was proceeded in the same manner as in Example 1 - (1) to obtain 4- (2-ethyl-3-acetoxybutyl) phenyl methyl ketone.

Kp 0.15 mmHg / 118 to 123 ⁰ C

IR (pure) a:,} _C _ _Q 1670 (aromatic ketone)

OcIo ¹⁷² ° ( ^ester )

(2) Using 4- (2-ethyl-3-acetoxybutyl) phenyl methyl ketone obtained above was proceeded in the same way as in Example 1 - (2) and (3) to obtain 2- / 4- (2-Athy1-3-hydroxybutyl) phenyl7propionaldehyde to obtain.

IR (neat) cm "" ¹ : j _{Q = Q} 1710 (aldehyde) MS m / e: 234 (M ⁺ ), 187 (M ⁺ - (CHO + H ₂

(3) In 200 ml of an ethanol solution containing 2.3 g of 2- / 4- (2-ethyl-3-hydroxybutyl) phenyl7propionaldehyde 20 ml of an aqueous solution containing 5 g of AgITCU were introduced and further 55 ml of a ti-1 sodium hydroxide solution were gradually added added with stirring.

After the mixture was stirred for 6 hours, it was filtered. The piltrate was then concentrated by evaporation in vacuo and washed with diethyl ether, / aischleessend the material was obtained by adding diluent

2 6 i 7 S 9

acidified ter hydrochloric acid and extracted with diethyl ether. The diethyl ether extract was washed with water and dried and evaporated in Takuum, with 2 g

were obtained in a / m yield of 80 fo .

The product was made from a mixed solvent of diethyl ether and η-hexane were recrystallized to obtain pure crystals.

P 100 to 103 ⁰ O

Elemental analysis for C ₁ CjH ₂₂ O ₅ :

calc .: 0 71.97 5ί, Η 8.86 £ found: C 71.79 #, H 8.89 %

IR (EBr) cm "" ¹ : £ _{G = Q} 1700 (-000H)

OO-H

3450 (-0H)

Example 4

Preparation of 2- / 4 ~ (2-ethyl-3-oxobutyl) phenyl7propionic acid

(1) Using (2-ethyl-3-oxobutyl) benzene, in followed the same manner as in Example 1 - (1) to obtain 4- (2-ethyl-3-oxobutyl) phenyl methyl ketone.

Ep 111 to 116 ⁰ C / 0.15 mmHg

IR (pure) cm "": ^ _C _ _Q 1670 (aromatic Eeton)

C = O ¹ 7 °° (aliphatic eetone)

(2) Using 4- (2-ethyl-3-oxobutyl) phenyl methyl ketone obtained above was carried out in the same manner as in Example 2 - (2) to prepare 4- (2-ethyl-3-ethylenedioxybutyl) ienylmethy! ketone su received.

Γ 115 to 123 ⁰ C / 0.1 mm%

IR (pure) cm ~ ί \ j ~ q 1670 (aromatic etone)

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(3) Using 4- (2-ethyl-3-ethylenedioxybutyl) phenyl methyl ketone obtained above was carried out in the same way as in Example 2 - (3) and (4) to prepare 2- / 4- (2-ethyl-3-oxobutyl) phenyl7propioiialdehyde to obtain.

IR (neat) cm "" ¹ : J _{G = o} .1710 MS m / e: 232 (M ⁺ ), 203

(4) In 200 ml of an ethanol solution containing 2.3 g of 2- / 4- (2-ethyl-3-oxobutyl) phenyl7propionaldehyde, 20 ml of an aqueous solution containing 5 g of AgITO ,, were introduced and further were while stirring gradually 55 ml of an in-1 sodium hydroxide solution admitted.

After the mixture was stirred for 6 hours, it was filtered, subsequently the filtrate was concentrated by evaporation in vacuo and washed with diethyl ether. Afterward the material obtained was acidified by the addition of dilute hydrochloric acid and diethyl ether extracted. The diethyl ether extract was washed with water and dried and evaporated in vacuo, whereby 2 g 2- ^ 4- (2-ethyl-3-oxobutyl) phenyl7propionic acid crude product in a yield of $ 80.

Then the product was purified by column chromatography (silica gel) to give 1.6 g of a pure oil to obtain.

IR (neat) cnT ¹ : J _{c =} 0.1690 (-COOH,> CO).

609846/1050

Claims (7)

Claims 1J compounds of the general formula 1 2 where R is a hydrogen atom and R is a hydroxy 1 2 represents a group or R together with R represents an oxo group, R represents a lower alkyl group, P1 represents an hydrogen atom or represents a lower alkyl group and R ^ represents a lower alkyl group, and its non-toxic Salts. 2. Compounds according to .Anspruch 1, characterized in that Br and Έτ represent methyl groups. 3. Compounds according to claim 1, characterized in that R and R are methyl groups
A * thy! Group represents. R and R represent methyl groups and R ⁴ ″ a methyl or 4. Process for the preparation of compounds of the general formula -CH-COOH 1 2 where R is an ¥ hydrogen atom and R is a hydroxy 1 2 represents a group or R together with R represent an oxo group, R ^ represents a lower alkyl group, R ^ a water atom or a lower alkyl group and R ^ is a low-alky! group, and their non-toxic salts, characterized in that a connection of the general 609846/1050 a formula ft R ¹ v / orin R ¹ , R ² , R ⁵ , R ⁴ "and R ^{5 have} the meaning given above, oxidized. 5. Pharmaceutical compositions, characterized in that they contain as active ingredient at least one compound according to claim 1, optionally together with a pharmaceutically acceptable carrier. 6. Pharmaceutical compositions in dosage form for the therapeutic administration, characterized in that it contains 10 to 200 mg of an active ingredient per unit Compound according to claim 1 together with a pharmaceutically ■ acceptable carrier. 7. Pharmaceutical composition according to claim 5, characterized in that that the active ingredient is selected from the group consisting of 2- / 4- (2-Hethyl-3-hydroxybutyl) phenylj-propionic acid and 2- / 4- (2-ethyl-3-hydroxybutyl) phenyl-7-propionic acid. 609846/1050